Environmental Factors

Various environmental factors, such as UV light, heavy metals, organic solvents, and infections, influence a genetically susceptible host in triggering the expression of SLE. Exposure to UV light causes photosensitivity (more frequently in the white LE population) and is a known disease-exacerbating factor. UV light causes apoptotic cell death of keratinocytes and cell surface expression of autoantigens previously "hidden"in the cytoplasm or nucleus. Autoantigens presented on surface membrane blebs of discrete size become accessible for immune recognition and attack. The latter may result in local inflammation and the appearance in the circulation of autoantibodies. UV light irradiation of cultured human keratinocytes induced changes consistent with apopto-sis, and the autoantigens were clustered in two kinds of blebs of the cell surface membrane, the smaller blebs containing endoplasmic reticulum, ribosomes, and the (auto)antigen Ro/SSA and the larger blebs containing nucleosomal DNA, Ro/SSA and La/SSB, and the small ribonucleoproteins. UV-mediated apoptotic cell death may yield increased serum concentrations of autoantigens that activate immune cells. In addition, the activated apoptotic cascade may allow further degradation of autoantigens, which may lead to the exposure of cryptic and potentially more immunogenic antigens, which would permit expansion of the autoimmune response (see Chap. 2). UV light and ionizing irradiation, along with other apoptotic stimuli, lead to the generation of new phosphoproteins, which apparently act as autoantigens since they are recognized by lupus serum. These phosphoproteins associate with U1-snRNP and may, therefore, alter splicing of various genes. In addition, it is known that cell stress induced by exposure to radiation, heavy metals, toxins, and drugs causes activation of various kinases, including p38 and the Jun N-terminus mitogen-activated protein kinases, which may also contribute to this process. These studies are important in revealing the biochemistry of the stressed cell and its repercussions in the production of new autoantigens. In addition, the altered cell biochemistry may affect gene transcription in the immune cells, which may render them autoreactive. Such candidate genes may include adhesion and co-stimulatory molecules (ICAM-1,CD40L,etc.).

Clinical experience suggests that SLE may be initiated or may relapse after an infection, but, despite repeated efforts, a lupus-causing microorganism has never been identified. It has been hypothesized that infectious agents can disproportionately trigger an endogenously dysregulated immune system for the development or exacerbation of SLE. Among the common pathogens, the herpesvirus EBV has received the most attention. Antibodies against EBV have cross-reactivity with the lupus-specific autoantigen Sm. It was recently reported that newly diagnosed young patients with LE have a significantly higher percentage of seropositivity for EBV infection than controls. Other tested herpesviruses did not follow this pattern. EBV DNA was found in the lymphocytes of all 32 young patients with LE tested and two thirds of controls. Whether EBV-infected individuals become more susceptible to the development of LE or patients with LE are become more susceptible to EBV infection or whether a third factor increases susceptibility to both is currently not known.

Molecular mimicry between autoantigens and antigens expressed by viruses and other pathogens have been extensively considered in the pathogenesis of autoimmune diseases. Epitopes of the SLE-associated 60-kd Ro/SSA autoantigen share sequences with the vesicular stomatitis virus (VSV) nucleocapsid protein,which may explain the presence of anti-Ro/SSA antibodies. In addition, immunization of animals with VSV proteins causes production of anti-Ro/SSA autoantibodies and anti-VSV antibodies. Additional examples of molecular mimicry include that between the B/B' component of the Sm antigen and the human immunodeficiency virus type 1 p24 gag protein and the D component of the Sm antigen and the EBV nuclear antigen type 1 protein of EBV.

Alternatively, viral infection can break tolerance to self-antigens, as was shown in transgenic mice expressing a VSV glycoprotein. Autoantibodies to VSV glycoprotein cannot be induced by VSV glycoprotein in adjuvant or by recombinant vaccinia virus expressing VSV glycoprotein, but they are triggered by infection with wild-type VSV. The latter is an attractive mechanism because it can explain disease flares that follow infections.

Viral proteins may interfere with the function of proteins involved in cell death and survival. For example, adenoviral proteins may activate or inhibit p53 and bcl-2. Interestingly, viral proteins may mimic chemokine receptors or ligands. These examples further complicate elucidation of the pathogenic involvement of viruses and other infectious agents in the development of the autoimmune response.

The syndrome of drug-induced LE has many similarities, but also important differences, to the idiopathic SLE syndrome. Because it represents a disease entity wherein the inciting factor is known, it is a good model to study certain aspects of SLE pathogenesis. Drugs that cause the SLE-like syndrome have been reported to induce DNA hypomethylation. Lupus T-cell DNA is hypomethylated, and the activity of the methylation-inducing enzyme DNA methyltransferase is decreased. Non-T cells from patients with SLE did not share this abnormality, which affected only half of the patients tested, and, moreover, this abnormality was not disease specific. Treatment of T cells with DNA methylation inhibitors induces up-regulation of the adhesion/co-stimulatory molecule lymphocyte function-associated antigen (LFA)-1. The significance of this event is underscored by studies in animal models in which infusion of T cells overexpressing LFA-1 can mediate the production of anti-dsDNA autoantibodies and the appearance of glomerulonephritis. It is thus possible that drugs inducing DNA hypomethylation can initiate an autoimmune process by up-regulating the co-stimulatory molecule LFA-1 (Dighiero and Rose 1999, Tsokos and Boumpas 2002).

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